Abstract
Cardiac gene expression of atrial natriuretic peptide (ANP) and that of
brain natriuretic peptide (BNP) are markedly elevated after myocardial
infarction. The cellular distribution and temporal responses of ANP and
BNP messenger RNA (mRNA) expression were compared by in
situ hybridization for 5 weeks after left coronary artery
ligation in sheep. Ligation resulted in highly reproducible,
transmural, left ventricular infarcts. Within the infarct, ANP mRNA
appeared from 7 days after ligation, whereas BNP expression was
undetectable in the infarct at any time. The cells synthesizing ANP
were shown by in situ hybridization and
immunocytochemistry to be fibroblasts invading the infarct. The
appearance of ANP expression coincided with the transition of these
cells to the myofibroblast phenotype. Treatment of cultured cardiac
fibroblasts with transforming growth factor-β (10 ng/ml) induced the
expression of α-smooth muscle actin, characteristic of the
transformation to myofibroblasts, and raised ANP concentrations in the
medium. In the surviving myocardium of the left ventricle, ANP and BNP
expression increased in response to ligation, BNP mRNA was particularly
strong at the lateral margins of the infarct. In both left and right
atria, levels of BNP mRNA increased markedly over the first 18 h,
whereas levels of atrial ANP mRNA decreased over 3 days after
infarction. This is the first report of ANP expression and synthesis by
cardiac fibroblasts invading the fibrotic scar, suggesting that ANP may
be involved in regulating fibroblast proliferation during reparative
fibrosis.